Pharmacological science has maintained that there exists a structure-activity relationship in which the chemical structure of a compound of interest (drug) determines the pharmacological selectivity and potency of the drug See, for example, Ross E., chapter on “PHARMACODYNAMICS: MECHANISMS OF DRUG ACTION AND THE RELATIONSHIP BETWEEN DRUG CONCENTRATION AND EFFECT,” in Hardman J. D., et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th edition, pp. 29–41, McGraw-Hill, New York (1990), (hereinafter “Goodman and Gilman's 9th Edition”). In many instances, structural entities (pharmacophores) have been identified within the overall chemical structure of a drug, which are critical for the drug's specificity of action.
For example, when one examines the structure of several anticonvulsant agents such as diphenylhydantoin, phenobarbital, and carbamazepine, which have all been shown to inhibit the action of voltage-sensitive sodium channels in a use-dependent manner, (McNamara J. O., chapter on “DRUGS EFFECTIVE IN THE THERAPY OF THE EPILEPSIES,” in Goodman and Gilman's, 9th edition), one notes that these compounds all contain a diphenylureido group (or a group that can resemble a diphenylureido group in three dimensional space) as part of their overall structure. The structural characteristics of compounds acting at the strychnine insensitive glycine site of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor have also been examined and kynurenic acid derivatives have been defined as exemplary structures which can act as glycine antagonists at this site and inhibit the function of the NMDA receptor-gated ion channels (Leeson P. D., et al., “THE GLYCINE SITE ON THE NMDA RECEPTOR: STRUCTURE-ACTIVITY RELATIONSHIPS AND THERAPEUTIC POTENTIAL,” J. Med. Chem., 37 4053–4067 (1994).
Both the overactivity of voltage-sensitive sodium channels and NMDA receptor-gated ion channels has been implicated in CNS hyperexcitability states that arise from a diverse etiology ranging from epilepsy (McNamara J. O., chapter on “DRUGS EFFECTIVE IN THE THERAPY OF THE EPILEPSIES,” Goodman and Gilman's, 9th edition, pp. 461–486; MacDonald R. L. et al., chapter on “GENERAL PRINCIPLES: PRINCIPLES OF ANTIEPILEPTIC DRUG ACTION,” in Levy R., et al., Antiepiletic Drugs, 3rd edition, Raven Press, New York (1989), to ethanol withdrawal. Thus, a chemical compound containing both the pharmacophore which is considered important for inhibiting voltage-sensitive sodium channels and a pharmacophore effective in inhibiting the NMDA receptor-gated ion channels, and having the duality of action particularly important for controlling central nervous system (CNS) hyperexcitability arising from ethanol withdrawal, other drug withdrawal, and other pathological conditions would be highly desirable.
Ethanol belongs to a class of pharmacologic agents that also includes other sedatives and hypnotics, such as barbiturates and benzodiazepines. The chronic and excessive ingestion or administration of ethanol (beverage alcohol), other agents with a similar pharmacologic profile (e.g., benzodiazepines and barbiturates), and analgesics (opiates) produces significant changes in CNS function in human beings and other animals. These neuroadaptive changes in CNS function in response to the depressant actions of ethanol and other similar drugs or analgesic actions of opiates result from modification of the normal chemical communication within specific pathways which mediate information flow through assemblages of brain neurons. These significant changes in CNS function, in general, result in a withdrawal syndrome which includes signs of CNS hyperexcitability when the chronic ingestion or administration of ethanol, other CNS depressant drugs, or opiates is abruptly terminated.
The withdrawal syndrome includes such manifestations of CNS hyperexcitability as tremors, insomnia, anorexia, seizures, convulsions, etc. The presence of a withdrawal syndrome related to the termination of administration of ethanol or other drug, e.g., barbiturate, or morphine is prima facie evidence that the individual is physically dependent on the drug being chronically ingested/administered. See, generally, Tabakoff, B. et al., “BIOLOGY OF TOLERANCE AND DEPENDENCE,” in Tabakoff, B., et al., eds. Medical and Social Aspects of Alcohol Abuse, pp. 187–220, Plenum Press, New York (1983); and Jaffe, J. H., chapter on “DRUG ADDICTION AND DRUG ABUSE,” in Gilman, A. G., et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th edition, pp. 522–573, Pergamon Press, New York (1990) (hereinafter “Goodman and Gilman's, 8th Edition”). Also, Edwards, G. “THE ALCOHOL DEPENDENCE SYNDROME: A CONCEPT AS STIMULUS TO ENQUIRY,” British Journal of Addiction, 81 171–183, 1986; Wikler, G., “DYNAMICS OF DRUG DEPENDENCE: IMPLICATIONS OF A CONDITIONING THEORY FOR RESEARCH AND TREATMENT,” Arch. Gen. Psychiatry, 28 611–616 (1973) and others have written extensively that avoidance of signs and symptoms of ethanol and other drug withdrawal are the impetus for further drug-taking behavior, and relapse occurs, in part, as an attempt at self-medicating withdrawal signs. One can thus contemplate that an efficacious medication for treatment of addictive drug withdrawal would also be efficacious in promoting the termination of drug-taking behavior and preventing relapse in those individuals who stop ingesting alcohol or other drugs. There is currently no single class of compounds suitable for the treatment of drug withdrawal syndromes because the current therapies are with medications which have cross-dependence potential (e.g., benzodiazepines and methadone) or treat only a limited portion of the withdrawal syndrome (e.g., propranolol for ethanol withdrawal).
Current therapies include: (a) transfer to less efficacious compounds (e.g., methadone) for opiate withdrawal; (b) treatment with sympatholytics (e.g., the β-adrenergic receptor antagonist propranolol or the α2-adrenergic receptor agonist clonidine) for opiate or ethanol withdrawal; and (c) treatment with anxiolytics, neuroleptics or sedatives (e.g., benzodiazepines or barbiturates) for ethanol withdrawal.
Research has demonstrated that the signs and symptoms of ethanol, barbiturate, and opiate withdrawal syndromes are quite similar in humans and lower animal species. Because of this similarity, the underlying neurochemical mechanisms of the human manifestations of ethanol, barbiturate, and opiate physical dependence and drug withdrawal can be predictively studied in non-human mammalian animal species.
Studies have demonstrated that the chronic treatment of mice with ethanol or barbiturates results in the up-regulation of the function of the brain excitatory neurotransmitter systems (i.e., the neuronal systems which use glutamate as a neurotransmitter substance). See, for example, Grant, K. A., et al., “ETHANOL WITHDRAWAL SEIZURES AND THE NMDA RECEPTOR COMPLEX,” Eur. J. Pharmacol, 176 289–296 (1990); Rabbani, M. et al., “POSSIBLE INVOLVEMENT OF NMDA RECEPTOR-MEDIATED TRANSMISSION IN BARBITURATE PHYSICAL DEPENDENCE,” Brit. J. Pharmacol., 111 89–96, (1994). In particular, chronic exposure to ethanol or barbiturates results in an increased number of the receptors for glutamate known as the N-methyl-D-aspartate (NMDA) receptors. Similarly, the development of tolerance to and physical dependence on opiates has been shown to involve NMDA receptors. See, Elliott, K., et al., “N-METHYL-D-ASPARTATE(NMDA) RECEPTORS, MU AND KAPPA OPIOID TOLERANCE, AND PERSPECTIVES ON NEW ANALGESIC DRUG DEVELOPMENT,” Neuropsychopharmacol., 13 347–356 (1995).
The increase in NMDA receptor function has been linked at the molecular and cellular level with the generation of the characteristic signs of CNS hyperexcitability during withdrawal from drugs such as ethanol, barbiturates, or opiates. A number of compounds which are inhibitors of NMDA receptor function have been proposed and tested as treatments for the ethanol withdrawal syndrome. However, such medications, particularly agents acting as blockers of the NMDA receptor ion channel and those competing with glutamate at the glutamate binding site, have a significant drawback, since such NMDA receptor antagonists themselves interfere with cognitive function. See Collingridge, G. L., et al., “EXCITATORY AMINO ACID RECEPTORS IN THE VERTEBRATE CENTRAL NERVOUS SYSTEM,” Pharmacol, Rev., 40 143–210 (1989). Recent work has also suggested that the non-competitive NMDA receptor antagonist, dizocilpine maleate (MK-801), reduces the development of morphine tolerance as well as the effects of withdrawal (Trujillo, K. A. et al., “EXCITATORY AMINO ACIDS AND DRUGS OF ABUSE: A ROLE FOR N-METHYL-D-ASPARTATE RECEPTORS IN DRUG TOLERANCE, SENSITIZATION AND PHYSICAL DEPENDENCE,” Drug Alcohol Depend., 38 139–154 (1995)), but only at doses which are known to induce marked behavioral stimulation and ataxia.
The NMDA receptor glycine site antagonists have been introduced to overcome some of the negative effects of the other NMDA receptor antagonists. See Lesson, P. D., et al., “THE GLYCINE SITE ON THE NMDA RECEPTOR: STRUCTURE-ACTIVITY RELATIONSHIPS AND THERAPEUTIC POTENTIAL,” J. Med. Chem., 37 4053–4067 (1994). Such agents do possess some anticonvulsant activity (Rowley, M., et al., “3-ACYL-4 HYDROXYQUINOLINE-2(1H)-ONES. SYSTEMICALLY ACTIVE ANTICONVULSANTS ACTING BY ANTAGONISM AT THE GLYCINE SITE OF THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX, ” J. Med. Chem., 36 3386–3396 (1993)), but the prototypical members of this class of agents, the R-(+) isomer of 3-amino-1-hydroxypyrrolidin-2-one, (±)HA-966, and 7-chlorokynurenate, have demonstrated a relative ineffectiveness at reducing or preventing the signs and symptoms of opiate withdrawal (Kosten, T. A., et al., “THE SEVERITY OF NALOXONE-PRECIPITATED OPIATE WITHDRAWAL IS ATTENUATED BY FELBAMATE, A POSSIBLE GLYCINE ANTAGONIST,” Neuropsychopharmacology, 13 323–333 (1995)) and ethanol withdrawal.
In generalized neuroexcitability disorders, that include drug withdrawal and some forms of epilepsy, two distinct phenomena important to the generation of seizures can be distinguished, i.e., initiation (development of seizure focus) and propagation (spread of seizure to contiguous and distant anatomical sites. See Rall, T. W., et al., chapter on “DRUGS EFFECTIVE IN THE THERAPY OF THE EPILEPSIES” in Goodman and Gilman's, 8th edition, pp. 436–462. Blockade of generalized seizure initiation is amenable to therapeutic strategies employing NMDA receptor antagonists (Croucher, M. J., et al., “7-CHLOROKYNURENIC ACID, A STRYCHNINE-INSENSITIVE GLYCINE RECEPTOR ANTAGONIST, INHIBITS LIMBIC SEIZURE KINDLING,” Neurosci. Lett., 118 29–32 (1990)). Agents which block propagation of neuroexcitability by blocking, in a use-dependent manner, voltage-sensitive sodium channels, have been used to block propagation and control epilepsy-related generalized seizures. These compounds have low levels of sedation, but the aura associated with initiation events is not controlled by such agents.
Carbamazepine is prototypic of the general class of voltage-sensitive sodium channel blockers and although it has been employed to treat ethanol withdrawal in humans, its effectiveness is equivocal (Erstad, B. L., et al., “MANAGEMENT OF ETHANOL WITHDRAWAL,” Am. J. Health-Syst. Pharm., 52 697–709 (1995)). Animal studies show that carbamazepine is not effective in reducing, by itself, the signs and symptoms of ethanol withdrawal (Grant K. et al., “COMPARISON OF THE EFFECTS OF THE UNCOMPETITIVEN-METHYL-D-ASPARTATE ANTAGONIST (±)-5-AMINOCARBONYL-10, 11-DIHYDRO-5H-DIBENZO [A,D]CYCLOHEPTEN-5,10-IMINE (ADCI) WITH ITS STRUCTURAL ANALOGS DIZOCILPINE (MK-801) AND CARBAMAZEPINE ON ETHANOL WITHDRAWAL SEIZURES,” J. Pharmacol. Exp. Ther., 260 1017–1022 (1992)).
Physical dependence on ethanol and other sedatives or hypnotics can generate deleterious effects on the CNS in addition to generating signs of withdrawal. A significant portion of the brain damage evident in alcoholics is likely to be the cumulative result of multiple withdrawal episodes during the lifetime of these individuals. The deleterious effect of ethanol withdrawal on brain morphology has been demonstrated. See, for example, Brandao, F., et al., “PIRACETAM IMPEDES HIPPOCAMPAL NEURONAL LOSS DURING WITHDRAWAL AFTER CHRONIC ETHANOL INTAKE,” Alcohol, 12 279–288 (1995); and Daryanani, H. E., et al., “ALCOHOLIC WITHDRAWAL SYNDROME AND SEIZURES,” Alcohol & Alcoholism, 29 323–328 (1994).
The deleterious effects of ethanol dependence and withdrawal have also been demonstrated in in vitro studies in which neurons exposed chronically to ethanol in culture are more susceptible to excitotoxic effects of glutamate, following ethanol withdrawal. See, for example, Iorio, K. R., et al., “GLUTAMATE-INDUCED NEUROTOXICITY IS INCREASED IN CEREBELLAR GRANULE CELLS EXPOSED CHRONICALLY TO ETHANOL,” Eur. J. Pharmacol., 248 209–212 (1993); Ahern, K. B., et al., “ENHANCEMENT OF NMDA TOXICITY AND CALCIUM RESPONSES BY CHRONIC EXPOSURE OF CULTURED CORTICAL NEURONS TO ETHANOL,” Neurosci. Lett., 165 211–214 (1994); and Chandler, L. J., et al., “CHRONIC ETHANOL EXPOSURE POTENTIATES NMDA EXCITOTOXICITY IN CEREBRAL CORTICAL NEURONS,” J. Neurochem., 60 1578–1581 (1993).
The increased excitotoxicity in the ethanol-withdrawn cells has also been explained by the up-regulation of the number of NMDA receptors caused by chronic exposure of the neurons to ethanol. Thus, there is a need for medications to treat dependence on or prevent the withdrawal syndrome from ethanol (or barbiturate) usage that beneficially ameliorate ethanol withdrawal-induced neuronal damage.
Since the pharmacological specificity of a chemical compound is determined by structural entities (pharmacophores) which are part of the overall structure of the pharmacologically active agent, an ideal compound would combine two or more pharmacophores with specific pharmacological properties to embody the pharmacological properties of both pharmacophores. In particular, a compound designed to possess, in one molecule, properties to both block voltage-sensitive sodium channels and to antagonize the glycine site of the NMDA receptor would be of far greater utility in controlling drug withdrawal CNS hyperexcitability than agents currently available. This invention provides a series of novel compounds that embody such pharmacological properties.